The present invention involves an improved process for the alleviation of anxiety by treatment with an anxiolytically effective amount of 6-hydroxy-8-[4-[4-(2-pyrimidinyl)-piperazinyl]-butyl]-8-azaspiro[4.5]-7,9- dione. This compound was first disclosed by Jajoo, et al., Drug Metab. and Disposition, 17/6, pp. 634-640, 1989, as being one of several metabolites of the clinically useful anxiolytic drug, buspirone. Confirmation of structure for this metabolite was achieved by comparison with an authentic sample of the compound prepared synthetically. This metabolite compound has been designated BMY 28674, and is also known as BMY 28674.
The parent drug, buspirone, has the following chemical structure. ##STR1##
Buspirone, chemically: 8-[4-[4-(2-pyrimidinyl)1-piperazinyl]butyl-8-azaspiro(4,5)-decane-7,9-dion e, is a pharmaceutically active compound which has been found to be effective for the treatment of anxiety disorders and depression. It is accepted that buspirone exerts its effects through the serotonin 1A (5-HT1A) receptor. However, buspirone shows a very high first pass metabolism and, in general, only about 4% of a therapeutic dose of buspirone reaches the systemic circulation in non-metabolized form after oral administration (Mayol, et al., Clin. Pharmacol. Ther., 37, p. 210, 1985). Large differences in buspirone absorption between individuals have also been observed. This has been demonstrated by variations of the maximum plasma concentration of drug in individuals by up to 10-fold differences (Gammans, et al., American J. Med., 80, Suppl. 3B, pp. 41-51, 1986).
Synthesis of buspirone and related analogs and disclosure of their psychotropic properties are described by Wu, et al., in U.S. Pat. No. 3,717,634. The use of buspirone hydrochloride as a novel antianxiety agent for the treatment of neurotic patients is described by Casten, et al., in U.S. Pat. No. 4,182,763.
BMY 28674 was previously tested for antianxiety properties using laboratory methods specifically developed for the measurement of antianxiety properties in azapirone compounds such as buspirone, gepirone and structural analogs. No significant antianxiety activity was ever detected for BMY 28674 in this testing. No significant biological activity of any type has ever been disclosed for this compound. Indeed, with the exception of 1-pyrimidinylpiperazine (1-PP), no significant antianxiety activity has been disclosed for any of the known buspirone metabolites. See: Gammans, et al., JAMA, (March, 1986), Vol. 80, Supp. 3B, pp. 43-44. As a consequence, oral dosing of buspirone for treating anxiety has been believed to be optimized when done in a manner to maximize the concentration of unchanged drug at the expense of metabolites.
In U.S. Pat. No. 5,431,922 an extended-release formulation of buspirone was described as providing an improvement in oral administration of the drug on the basis that blood levels of unchanged buspirone were increased while metabolite levels were reduced as measured by the ratio of plasma levels of buspirone to the 1-PP metabolite. However, no efficacy data were ever disclosed for these formulations nor were they commercialized.
U.S. Pat. No. 5,633,009 disclosed and claimed a transdermal patch for delivering buspirone. The transdermal delivery, as expected, reliably gave higher buspirone blood levels (AUC) with much reduced metabolite levels, as measured by 1-PP. A typical patch was designed to deliver 60 mg of buspirone per 24 hour period. Surprisingly, clinical studies conducted with this patch demonstrated an anxiolytic effect that was not distinguishable from placebo.
Most recently an improved method for oral administration of buspirone was claimed in U.S. Pat. No. 6,008,222 wherein the bioavailability of unchanged buspirone is increased and metabolite formation is decreased. The disclosed method involved co-administration of buspirone with the drug nefazodone, an inhibitor of cytochrome P4503A4 (CYP3A4). Based on assessment of preliminary clinical data, no further development of this drug combination pharmaceutical formulation has been planned.
In summary, while BMY 28674 has been found to be one of several human metabolites resulting from oral administration of the anxiolytic drug, buspirone, no useful biological activity has previously been associated with the compound itself prior to the present invention. In particular, no anxiolytic activity was detected in previous testing. Dosing recommendations for buspirone have been made in accordance with the expectation that inhibition of buspirone's metabolism would generate a more robust antianxiety response. The clinical observation that a certain percentage of anxious patients do not get relief from administration of buspirone has been ascribed to insufficient levels of parent drug being achieved in these non-responders. A second clinical observation regarding a seven to ten day lag period prior to observation of an anxiolytic effect has been attributed to a requirement for a change in receptor site dynamics as a result of chronic buspirone administration. The unexpected discovery of the anxiolytic effects of BMY 28674 suggests other explanations for these observations.